Method for treating cancer using camptothecin derivatives and 5-fluorouracil

ABSTRACT

A combination therapy for treating cancer including administering at least one camptothecin derivative in conjunction with another anticancer agent. The combination therapy is preferably used as a first-line therapy for treating metastatic colorectal cancer and preferably involves administration of a combination of CPT-11, 5-fluorouracil and folinic acid, according to specific infusional treatment schedules which show therapeutic synergy in the treatment of cancer.

[0001] This application is a continuation of U.S. application Ser. No.10/124,458, filed Apr. 18, 2002, now allowed, which is a continuation ofSer. No. 09/559,737, filed Apr. 28, 2000, now U.S. Pat. No. 6,403,569B1, issued, Jun. 11, 2002, which claims the benefit of U.S. ProvisionalApplication No. 60/131,678, filed Apr. 29, 1999, all of which areincorporated herein by reference in their entirety.

BACKGROUND OF THE INVENTION

[0002] 1. Field of the Invention

[0003] This invention relates to an improved treatment for cancercomprising administering a combination of at least one camptothecinderivative and at least one other colorectal anticancer drug. Morespecifically, the invention relates to treatments for colorectal cancercomprising administering a synergistic therapeutically effectivecombination of Campto® (CPT-11, Irinotecan), 5-fluorouracil (5-FU), andfolinic acid (FA).

[0004] 2. Description of the Art

[0005] Colorectal cancer is a leading cause of morbidity and mortalitywith about 300,000 new cases and 200,000 deaths in Europe and the USAeach year [Boyle P., Some recent developments in the epidemiology ofcolorectal cancer In: Bleiberg H., Rougier P., Wilke H. J., eds;Management of colorectal cancer London: Martin Dunitz: 19-34 (1998) andMidgley R. S., Kerr D. J., Systemic adjuvant chemotherapy for colorectalcancer In: Bleiberg H., Rougier P., Wilke H. J., eds.; Management ofcolorectal cancer: London: Martin Dunitz, 126-137 (1998)]. Althoughabout fifty percent of patients are cured by surgery alone, the otherhalf will eventually die due to metastatic disease, which includesapproximately 25% of patients who have evidence of metastases at time ofdiagnosis.

[0006] In the United States, there are currently about 130,000 patientswith colorectal cancer, 95,000 with colon cancer and 35,000 with rectalcancer. [American Cancer Society. Cancer Facts and Figures 2000.] Ofthese patients, 20% have metastatic disease at presentation, 40% willultimately develop metastases, and 57,000 patients will die due tometastatic disease. [Id.].

[0007] 5-FU has been the mainstay of chemotherapy for colorectal cancerfor four decades. It has been shown to improve both survival time (11months versus 5 months) and quality of life of patients with metastaticdisease, when compared to no antitumor therapy [J. Clin. Oncol., 10(6),904-11 (1992) and Br. Med. J., 306, 752-55 (1993)].

[0008] Insights into 5-FU molecular pharmacology have led to severalstrategies to modulate its cytotoxic effects. Infusional versus bolusadministration of 5-FU resulted in a higher response rate (22% v. 14%)but did not significantly effect the median survival time (12.1 monthsv. 11.3 months). [Meta-analysis Group in Cancer. J. Clin Oncol. 1988;16:301-308.] The most successful approach has been the coadministrationof 5-FU with folinic acid (FA), which increases the degree of inhibitionof thymidylate synthase [G. J. Peters, C. L. van der Wilt, C. J. vanGroeningen et al; Thymidylate synthase inhibition after administrationof fluorouracil with or without Leucovorin in colon cancer patients:implications for treatment with fluorouracil; J. Clin Oncol, 12, no. 10:2035-2042 (1994)], depletes cellular thymidine, and induces apoptosis[C. Benz and E. Cadman; Modulation of 5-fluorouracil metabolism andcytotoxicity by antimetabolite pretreatment in human colorectaladenocarcinoma HCT-8; Cancer Res, 41, 994-999, (1981)]. Folinic acid hasbeen approved in numerous European countries for the treatment ofcolorectal cancer. Among the various modulations and schedules ofadministration, high dose infusional regimens of 5-FU plus folinic acid(5-FU/FA) are widely used in Europe and have resulted in the highestresponse rates (up to 44%) and longest time to progression (around 7months) and median survival (up to 16.6 months) over administration ofbolus 5-FU/FA (J. Clin. Oncol, 15 (2), 808-815 (1997); J. Clin. Oncol,16(2), 418-426 (1998); Ann of Oncol, 9, 727-731 (1998); Onkologie,21,403-307 (1988).

[0009] European patent EP 137,145, the disclosure of which isincorporated herein by reference, describes camptothecin derivatives ofthe formula:

[0010] wherein:

[0011] R₁ is selected from hydrogen, halogen and alkyl;

[0012] X is selected from a chlorine atom and NR₂R₃, wherein R₂ and R₃,which may be identical or different, are selected from a hydrogen atom,optionally substituted alkyl radicals, carbocycles and heterocycleswhich are optionally substituted, and optionally substituted alkylradicals, and form, with the nitrogen atom to which they are attached, aheterocycle optionally containing another heteroatom selected from O, Sand/or NR₄, R₄ being selected from a hydrogen atom and alkyl radicals;and

[0013] wherein the group X—CO—O— is located in position 9, 10 or 11 onring A. These camptothecin derivatives are anticancer agents whichinhibit topoisomerase I. CPT-11, also known as Irinotecan, whereinX—CO—O— is [4-(1-piperidino)-1-piperidino]carbonyloxy, is a particularlyeffective agent in the treatment of solid tumors and, in particular,colorectal cancer.

[0014] The European patent application EP 74,256, the disclosure ofwhich is incorporated herein by reference, also describes camptothecinderivatives which are mentioned as anticancer agents, in particularderivatives of structures analogous to the structure given above and inwhich X—CO—O— is replaced with a radical —X′R′ for which X′ is O or Sand R′ is a hydrogen atom or an alkyl or acyl radical.

[0015] Other camptothecin derivatives have also been described, forexample, in the patents or patent applications EP 56,692, EP 88,642, EP296,612, EP 321,122, EP 325,247, EP 540,099, EP 737,686, WO 90/03169, WO96/37496, WO 96/38146, WO 96/38449, WO 97/00876, U.S. Pat. No.7,104,894, JP 57 116,015, JP 57 116,074, JP 59 005,188, JP 60 019,790,JP 01 249,777, JP 01 246,287 and JP 91 012,070 or in Canc. Res., 38(1997) Abst. 1526 or 95 (San Diego-12-16 April), Canc. Res., 55(3),603-609 (1995) or AFMC Int. Med. Chem. Symp. (1997) Abst. PB-55(Seoul-27 July-1 August), the disclosure of each of these isincorporated herein by reference.

[0016] Camptothecin derivatives are usually administered by injection,more particularly intravenously in the form of a sterile solution or anemulsion. Camptothecin derivatives can also be administered orally, inthe form of solid or liquid compositions containing the art recognizedadjuvants and/or excipients.

[0017] CPT-11, a camptothecin-derivative, is one of the most active newagents in colorectal cancer. In patients resistant to 5-FU, single agentCPT-11 tested in two large phase III randomized trials resulted in alonger survival and a better quality of life compared with supportivecare only [D. Cunningham, S. Pyrhonen, R D. James et al, The Lancet,352, 1413-1418 (1998)]. CPT-11 also resulted in a longer survivalwithout deterioration in quality of life compared with 5-FU/FAinfusional regimens [P. Rougier, E. van Cutsem et al The Lancet, 352,1407-1412 (1998)]. CPT-11 has thus been identified as the referencetreatment in metastatic colorectal cancer after failure with prior 5-FUtreatment.

[0018] CPT-11 has also been shown to be at least as active as theso-called standard 5-FUIFA bolus treatment in chemotherapy naivepatients with metastatic colorectal cancer. Single-agent CPT-11,administered intravenously at 125 mg/m² in two separate studies,resulted in a response rate of 32% and 26% respectively. Median survivalwas 12.1 months and 11.8 months respectively. [J. Clin Oncol, 14(3),709-715 (1996); J. Clin Oncol, L5(8) 2910-2919(1997)]. Other studiessuggest that CPT-11 may extend survival when used as a second-linetherapy in combination with either best supportive care or an infusionalbased 5-FU regimen. [Cunningham et al. The Lancet. 1998; 352; 1413-18;Rougier et al. The Lancet. 1998; 352; 1407-12.]

[0019] A study relating to CPT-11 published by D. Cunningham, Eur. J.Cancer, 32A suppl. 3: S1-8 (1996) suggests that CPT-11 offers adifferent cytotoxic approach, topoisomerase I inhibition, that maycomplement the use of 5-FU/folinic acid in colorectal cancer in thefuture.

[0020] In addition, combinations of CPT-11 and 5-FU have already beenstudied in phase I studies in Japan, indicating in preliminary resultsthat concurrent administration is feasible in terms of safety [L. Saltzet al., Eur. J. Cancer 32A, suppl 3 : S24-31 (1996); Saltz, J. ClinOncol. 1996, 14:2959-2967; Ducreux, J. Clin Oncol. 1999, 17: 2901-08;Vanhoefer, J Clin Oncol. 1999, 17: 907-13]. At the present time,however, it has never been reported that combinations of CPT-11 and 5-FUcan lead to a significant, even therapeutically synergistic increase, ofefficacy in the treatment of cancer.

[0021] All of the references described herein are incorporated herein byreference in their entirety.

SUMMARY OF THE INVENTION

[0022] In this application, specific administered doses combined withspecific schedules of administration of a combination led to asignificant increase of efficacy in the expected clinical response. Inother words, it is shown that the combination of CPT-11, 5-FU and FAdemonstrates therapeutic synergy. A combination manifests therapeuticsynergy if it is therapeutically superior to one or the other of theconstituents used at its optimum dose.

DETAILED DESCRIPTION OF THE INVENTION

[0023] It has now been found that administering a CPT-11combination-based therapy according to certain treatment schedules istherapeutically synergistic for the treatment of cancer, particularlycolorectal cancer. Specifically, it has been found that a combination ofCPT-11, 5-FU, and FA results in an increase in clinical responsesgreater than expected and higher than for 5-FU/FA alone, whether thecombination is administered via a bolus regimen or infusional regimens.The responses are even greater however when the combination isadministered by infusion, according to either the AIO treatmentschedule, in which the combination is administered weekly, or the deGramont treatment schedule, in which the combination is administered intwo week intervals.

[0024] The clinical study which compared the infusional combinationCPT-11, 5-FU/FA treatment with 5-FU/FA alone, was conducted in 83 sites,primarily in Europe. Patients were enrolled for the experimental andcontrol arms of both the AIO and de Gramont regimens from May 1997 toFebruary 1998. The survival cut-off date was October 1999, which allowedfor a 20-month follow-up of survival-and post-study chemotherapy.

[0025] The primary objective of the study was evaluation of the responserate in patients with metastatic colorectal cancer previously untreatedwith chemotherapy for advanced disease. In addition to response rate,the sample size in the study allowed observation of a significantimprovement of time to progression by 50% (6 months versus 9 months).Survival rate, safety, and quality of life were also evaluated.

[0026] In setting up this study, at least 338 patients were considerednecessary to show a statistically significant difference in responserate between patients treated with 5-FU/FA alone (at least 169 patients)and patients treated with CPT-11 in combination with the same scheduleof 5-FU/FA (at least 169 patents), assuming a 40% improvement inresponse rate.

[0027] Patients who were eligible had a histologically provenadenocarcinoma of the colon or rectum, had unresectable measurablemetastases, a performance status of 0, 1 or 2, had no prior chemotherapyfor metastatic disease, had adequate hematologic, renal and hepaticfunction, and had completed any adjuvant 5-FU treatment more than sixmonths prior to entry into the study. Metastatic colorectal cancerpatients who had documented progression after at least one 5-FU regimenfor advanced disease were accepted. Prior pelvic radiation waspermitted.

[0028] In the CPT-11/5-FU/FA arm of the clinical trial, the median agewas 62 years old, ranging from 2 to 75; the gender of the patients was67% female and 33% male; and the performance status of the patients was52% at 0 and 48% at greater than or equal to 1. Among these patients,the colon was the primary cancer site in 55% of the patients and therectum in 45% of the patients. For 62% of the patients, the number oforgan sites involved was 1 and for the remaining 38%, the number oforgan sites involved was greater than or equal to 2. Seventy-sevenpercent of the patients also had liver involvement. For these CPT-11combination-based patients, the median time from initial diagnosis was4.5 months, the range being 0.1 to 88 months. Twenty-six percent hadreceived 5-FU as prior adjuvant therapy; and 20% had receivedradiotherapy.

[0029] In the 5-FU/FA control arm, the median age was 61 years old,ranging from 25 to 75; the gender of the patients was 53% female and 47%male; and the performance status was 51% at 0 and 49% at greater than orequal to 1. In these patients, the colon was the primary cancer site in65% of the patients and the rectum in 36% of the patients. For 63% ofthe patients, the number of sites involved was 1, and for 37% of thepatients, the number of sites involved was greater than or equal to 2.Eighty percent of the patients also had liver involvement. For these5-FU/FA patients: (i) the median time from initial diagnosis was 2.7months, ranging from 0.1 to 104 months. Twenty-four percent had received5-FU as a prior adjuvant therapy and 16% had received radiotherapy.

[0030] Baseline abnormalities for the CPT-11/5-FU/FA population ascompared to the 5-FU/FA population was 16% v. 21% had Hgb less than 11g/dL; 47% v. 38% had WBC greater than or equal to 8×10⁹/L; 40% v. 44%had an LDH greater than the upper limit of normal; 7% in each arm hadbilirubin greater than the upper limit of normal; and 35% v. 32% had CEAgreater than or equal to 100 ng/mL.

[0031] Ultimately, the randomized patient enrollment, based on the abovecriteria, included 395 patients, 199 in the combined CPT-11/5-FU/FAstudy, and 186 in the 5-FU/FA study. Of the patients receiving CPT-11based combination therapy, 54 patients were treated according to the AIOregimen and 145 patients were treated according to the de Gramontregimen. Of the patients receiving only 5-FU/FA, 43 patients weretreated according to the AIO regimen and 143 patients were treatedaccording to the de Gramont regimen. The therapy was administered asfollows:

[0032] A. The AIO Treatment Schedule

[0033] 1. 5-FU/FA+CPT-11 treatment schedule-54 patients

[0034] FA 500 mg/m² i.v. was administered over 2 hours followed by theadministration of 5-FU (2300/2600 mg/m²) i.v. infusion over 24 hours,once a week for 6 weeks, which was followed by one week rest. (Thisseven week cycle is one cycle). For the same cycle, 80 mg/m² of CPT-11was administered by i.v. once a week for six weeks, followed by one weekof rest. Each cycle was reproduced until a progression (stabilization orimprovement in the disease) or unacceptable toxicity was observed.

[0035] 2. 5-FU/FA treatment schedule-43 patients

[0036] FA 500 mg/m² i.v. was administered over 2 hours followed by theadministration of 5-FU (2600 mg/m²) i.v. infusion over 24 hours, once aweek for 6 weeks, which was followed by one week rest. Each cycle wasreproduced until a progression or unacceptable toxicity was observed.

[0037] B. The de Gramont Treatment Schedule

[0038] 1. 5-FU/FA+CPT-11 treatment schedule-145 patients

[0039] On day 1, FA 200 mg/m² i.v. was administered over 2 hoursfollowed by the administration of 400 mg/m² 5-FU i.v. bolus and 600mg/m² 5-FU i.v. over 22 hours (one cycle) and administration of 180mg/m² CPT-11 i.v. On day 2, 200 mg/m² i.v. of FA was administered over 2hours. This regimen comprised one cycle. The same doses and regimen weregiven every 2 weeks until a progression or unacceptable toxicity wasobserved.

[0040] 2. 5-FU/FA treatment schedule-143 patients

[0041] On day 1, FA 200 mg/m² i.v. was administered over 2 hoursfollowed by the administration of 400 mg/m² 5-FU i.v. bolus and 600mg/m² 5-FU i.v. over 22 hours. On day 2, 200 mg/m² i.v. of FA wasadministered over 2 hours. The same doses and regimen were given every 2weeks until a progression or unacceptable toxicity was observed.

[0042] Supportive care was allowed in all treatment schedules andincluded atropine for the treatment of cholinergic symptoms, loperamidefor the treatment of late diarrhea, antiemetics for the prophylaxis ofnausea and vomiting, and flouroquinolone antibiotic for diarrhea inassociation with grade 4 neutropenia or neutropenic fever.

[0043] Before each infusion during the treatment period, a physicalexamination, WHO performance status, hematology, and biochemistry wereassessed. Radiological assessments to evaluate the antitumor responsewere performed following every cycle [every 6 weeks for the de Gramontschedule and every 7 weeks for the AIO schedule]. Thus, in-studyassessments included:

[0044] (i) tumor measurements every six or seven weeks, depending on theregimen;

[0045] (ii) evaluation of performance status, weight, quality of life(QLQ-C30), and chemistries on day one of each cycle; and

[0046] (iii) evaluation of adverse events and CBCs weekly.

[0047] A follow-up was also conducted of post-study chemotherapy andsurvival. RESULTS:

[0048] The phase III clinical trial described above demonstrated thetherapeutic superiority of combining CPT-11 with 5-FU/FA over 5-FU/FAalone using the same infusional regimens. Both the weekly AIO regimenand the every two weeks de Gramont regimen have shown similarefficacious results with significantly higher response rates and longertime to progression than treatment by bolus administration of 5-FU/FA(J. Clin. Oncol, 15 (2), 808-815 (1997); J. Clin. Oncol, 16(2), 418426(1998) ). Therefore, both regimens have established the combination ofCPT-11 with 5-FUIFA as the preferred first line treatment of colorectalcancer in Europe.

[0049] This phase III randomized study also demonstrated the superiorityof combining CPT-11 and 5-FU/FA infusional regimens over the sameregimens of 5-FU/FA alone in patients with metastatic colorectal cancerwho were previously untreated with palliative chemotherapy. A total of385 patients were randomized: 199 on CPT-11/5-FU/FA combination therapyand 186 on 5-FU/FA alone. The patient population randomized into thisstudy was representative of the usual patient population with metastaticcolorectal cancer suitable for CPT-11 chemotherapy.

[0050] A significantly higher response rate was observed with theCPT-11/5-FU/FA combination compared with 5-FU/FA alone: 49% versus 31%.Complete responses occurred only in the CPT-11 combination group inpatients with visceral involvement or soft tissue lesions. In a stepwisemultivariate analysis, the odds for response in patients receiving theCPT-11 combination was 2.6 times higher than for those receiving 5-FU/FAalone when adjusting for significant covariates (weight loss and timefrom diagnosis to first metastasis).

[0051] A significantly longer duration of response and stabilization wasalso observed in favor of the CPT-11 combination (8.6 months versus 6.2months).

[0052] Median time to progression (TTP) was also significantly longerwith the CPT-11 combination group, 6.7 months versus 4.4 months. In astepwise multivariate analysis, the risk for progression increased by62% with 5-FU/FA alone after adjustment for significant covariates (ageand liver involvement).

[0053] This trial demonstrates a survival advantage which was clinicallyrelevant with a median of 17.4 months with the CPT-11/5-FU/FAcombination versus 14.1 months with 5-FU/FA alone. This is among thelongest median survival times ever published with combinationchemotherapy in metastatic colorectal cancer in a multicentric setting.Further, this significant median survival advantage was obtained despitethe fact that further chemotherapy (administered to about 50% ofpatients) might have lowered the overall survival benefit.

[0054] Second line treatment was left to each investigator's decision inthe best interest of their patients. In fact, 49% of the CPT-11/5-FU/FApatients received second-line treatment: (i) 2% received CPT-11 basedtherapy; (ii) 4% received CPT-11 plus 5-FU based therapy; (iii) 32%received 5-FU based therapy; and (iv) 11% received other therapy. Inaddition, 65% of the 5-FU/FA patients received second-line therapy: (i)28% received CPT-11 based therapy; (ii) 6% received CPT-11 plus 5-FUbased therapy; (iii) 21% received 5-FU based therapy; and (iv) 10%received other therapy. Of note, 34% of patients in the 5-FU/FA groupreceived second line CPT-11 therapy which has been demonstrated to beefficacious. Nevertheless, the difference in survival between thepatients on combination therapy as opposed to 5-FU based therapy wasstill significant, underlining the importance of introducing CPT-11 infirst line treatment of patients with advanced colorectal cancer.

[0055] Both the weekly AIO and every 2 weeks de Gramont CPT-11combination regimens were shown to be feasible at the dose and scheduleinitially planned. The resultant median dose intensity (i.e. the ratioof actual dose intensity relative to planned dose intensity) wasactually lower than the planned dose intensity. For CPT-11/5-FU/FApatients under the AIO regimen, the median dose intensity was 0.82CPT-11 and 0.81 5-FU. For CPT-11 patients under the de Gramont regimen,the median dose intensity was 0.93 CPT-11 and 0.92 5-FU/FA. By contrast,the median dose intensity for 5-FU/FA patients under the AIO regimen was0.90 5-FU, and for those patients under the de Gramont regimen was 0.965-FU.

[0056] The median duration of treatment was slightly longer in theCPT-11 combination group compared with the 5-FU/FA alone group (5.5months versus 4.8 months in the weekly AIO regimen and 5.7 months versus4.2 months in the every two weeks de Gramont regimen, respectively). Thenumber of cycles (7-week duration on the weekly schedule and 6-weekduration on the every two weeks schedule) administered at the initialplanned dose were comparable between the CPT-11 combination group andthe 5-FU/FA group in each schedule (51.1% versus 50.6% on the weeklyschedule and 84.6% versus 82.7% on the every 2 weeks schedule).

[0057] With respect to adverse events, of the CPT-11/5-FU/FA patientpopulation, 23% had diarrhea, including 17% with grade 3 diarrhea and 6%with grade 4 diarrhea. In addition, 6% of the population had grade 3 or4 vomiting, 3% had grade 3 or 4 mucositis, 9% had grade 4 neutropenia,5% had neutropenic fever, and 2% had neutropenic infection. Finally,discontinuations were observed in 9% of the population and drug-relateddeaths occurred in 0.5% of the population.

[0058] This compared to the 5-FU/FA population as follows: 11% haddiarrhea, including 7% with grade 3 diarrhea and 4% with grade 4diarrhea; 6% of the population had grade 3 or 4 vomiting, 2% had grade 3or 4 mucositis, 9% had grade 4 neutropenia, 5% had neutropenic fever and2% had neutropenic infection. Finally, discontinuations were observed in3% of the 5-FU/FA population and no drug-related deaths occurred.

[0059] In a comparative bolus study of the combination of CPT-11/5-FU/FAversus 5-FU/FA alone, the median time of survival was 14.8 months forthe combination and 12.6 months for 5-FU/FA alone. In this study, CPT-11was also evaluated alone and the mean survival time was 12.0 months.Thus, administration of the combination by the bolus method, althoughclearly not as efficacious as the AIO and de Gramont infusional regimensdescribed above, was also therapeutically synergistic, since thecombination performed better than either of its component parts.

[0060] In summary, the study demonstrated that CPT-11 combinationtherapy sets a new standard in the first-line treatment of metastaticcolorectal cancer, indicating that CPT-11 should be indicated as acomponent of first-line therapy for patients with metastatic carcinomaof the colon or rectum. More specifically, in this first phase IIIrandomized trial using CPT-11 combination with 5-FU/FA, it was shownthat this combination treatment prolongs life without compromisingquality of life. Consistent significant advantage in terms of efficacyand clinical benefit i.e., response rate, median TTP, median TTF, mediantime to PS deterioration, median survival time and quality of life wereshown to be in favor of the CPT-11 combination group. No othercombination therapy had shown such a high antitumor efficacy over highdose infusional 5-FU/FA regimens at the time of starting this phase IIItrial.

[0061] It is to be understood that in the above-mentioned study, CPT-11has been administered by i.v. route, but could alternatively beadministered by oral route. If administered orally (p.o.) in either ofthe AIO and de Gramont regimens, CPT-11 would be administered at a doseof 60 to 70 mg/m² every day for 5 consecutive days, with the sameregimen reproduced every three weeks.

[0062] Currently, the CPT-11 combination is the only combination regimenin the treatment of metastatic colorectal cancer to demonstrate asurvival advantage and a consistency in anti-tumor efficacy over highdose infusional 5-FU/FA. The median survival time of 17.4 months isachieved, with a trend to a better quality of life, by using the CPT-11combination. This is a significant step forward in the management ofpatients with metastatic colorectal cancer.

[0063] Moreover, the superiority of the CPT-11 combination is achievedwith an acceptable and manageable safety profile even though moretoxicities occurred compared with 5-FU/FA alone. The risks representedby neutropenia and its complications, as well as diarrhea and mucositisare favorably counterbalanced by the high efficacy and better quality oflife achieved by the CPT-11/5-FU/FA combination infusional regimens.

[0064] Therefore, CPT-11 in combination with 5-FU/FA should beconsidered as the treatment of choice in first-line treatment ofpatients with advanced colorectal cancer.

[0065] The foregoing written description relates to various embodimentsof the present invention. Changes and modifications may be made thereinwithout departing from the spirit and scope of the invention as definedin the following claims.

What is claimed is:
 1. A method for treating a cancer in a patientcomprising administration of a combination of at least one camptothecinderivative, 5-fluorouracil (5-FU) and folinic acid (FA) to said patientin an amount and in a schedule of administration that is therapeuticallysynergistic in the treatment of said cancer and wherein said cancer iscolon, rectal or colorectal cancer.
 2. The method as set forth in claim1 wherein said cancer is colorectal cancer.
 3. The method as set forthin claim 1 wherein said cancer is colon cancer.
 4. The method as setforth in claim 1 wherein said cancer is rectal cancer.
 5. The method asset forth in claim 1 wherein said patient is having at least abouttwenty percent metastatic cancer.
 6. The method as set forth in claim 1wherein the administration of the combination is by infusion.
 7. Themethod as set forth in claim 1 wherein the administration of thecombination is by injection.
 8. The method as set forth in claim 1wherein the combination is administered intravenously.
 9. The method asset forth in claim 1 wherein the combination is administered orally. 10.The method as set forth in claim 1 wherein said camptothecin derivativeis of the formula:

wherein: R₁ is selected from hydrogen, halogen and alkyl; X is selectedfrom chlorine and NR₂R₃, wherein R₂ and R₃, which may be identical ordifferent, are selected independently from hydrogen, optionallysubstituted alkyl, carbocycle and heterocycle which are optionallysubstituted, and optionally substituted alkyl forms with the nitrogenatom to which it is attached a heterocycle optionally containing anotherheteroatom selected from O, S or NR₄, R₄ being selected from hydrogenand alkyl.
 11. The method as set forth in claim 10 wherein the groupX—CO—O— is located at position 9, 10 or 11 on ring A.
 12. The method asset forth in claim 10 wherein X—CO—O— is[4-(1-piperidino)-1-piperidino]carbonyloxy.
 13. The method as set forthin claim 1 wherein said camptothecin derivative is CPT-11.
 14. Themethod as set forth in claim 13, wherein said schedule comprises a cycleof: administering FA 500 mg/m² i.v. over 2 hours followed by theadministration of 5-FU (from 2300 to 2600 mg/m²) i.v. and 80 mg/m² ofCPT-11 over 24 hours, once a week for 6 weeks, followed by a one weekrest; and repeating said cycle until a progression or an unacceptabletoxicity is observed.
 15. The method as set forth in claim 14, whereinsaid method is a first-line therapy for metastatic colorectal cancer.16. The method as set forth in claim 14, wherein said method is afirst-line therapy for metastatic colon cancer.
 17. The method as setforth in claim 14, wherein said method is a first-line therapy formetastatic rectal cancer.
 18. The method as set forth in claim 13,wherein said schedule comprises administering a two-week cycle wherein:200 mg/m² of folinic acid is administered i.v. over two hours on daysone and two of said two-week cycle, 400 mg/m² of 5-FU is administered byi.v. bolus on day one of said two-week cycle and 600 mg/m² of said 5-FUis administered i.v. over 22 hours on day one of said two-week cycle,and 180 mg/m² of CPT-11 is administered i.v. on day one of said two weekcycle; and said two-week cycle is repeated until a progression or anunacceptable toxicity is observed.
 19. The method as set forth in claim18, wherein said method is a first-line therapy for metastaticcolorectal cancer.
 20. The method as set forth in claim 1, wherein saidat least one camptothecin derivative is CPT-11 and is administeredorally at the dose of from about 60 to 70 mg/m² daily for fiveconsecutive days, said schedule of CPT-11 administration beingreproduced every three weeks.